Cholangiocarcinoma is a hepatic biliary cancer of high morbidity and mortality, whose molecular pathogenesis is unknown. In addition, in contrast to hepatocytes, very little is known about how hyperplastic and neoplastic biliary epithelial cell proliferation in liver is regulated. Recently, we provided data strongly suggesting that preferential overexpression of tyrosine phosphorylated c-met and c-neu/erbB-2 tyrosine kinase growth factor receptors represent an early and significant change in cholangiocarcinoma pathogenesis in the furan rat model of intrahepatic biliary cancer development. We also recently reported on the immunohistochemical demonstration of c-met overexpression in the neoplastic epithelial of a significant percentage of human cholangiocarcinomas of Japanese origin compared with bile duct cells in age matched normal control livers. Moreover, very recent in situ hybridization and immunohistochemical results from our laboratory strongly suggest the possibility of an activated hepatocyte growth factor/c-met autocrine pathway as being a hallmark change associated with the development of cholangiocarcinoma in furan-treated rats. Based on these findings, we have hypothesized that alterations in expression of members of the epidermal growth factor family of receptors and of the hepatocyte growth pathway may play key roles in the development of cholangiocarcinoma in the furan rat model and also in the human. The experiments proposed in the current grant application are designed to link specific growth factor receptor/growth factor alterations in the furan rat model of cholangiocarcinogenesis with the human disease, with the intent of determining if they may also represent critical and significant changes in the pathogenesis of human hepatic biliary cancers of specific histiotype and cell proliferative activity. We will also address specific mechanisms that may be driving the overexpression of receptor genes like c-neu/erbB-2 and c-met in furan-induced rat cholangiocarcinomas compared with human cholangiocarcinomas of different ethnic origins and etiologies. Lastly, we will reinforce and expand our studies aimed at demonstrating specific formation of a hepatocyte growth factor/c- met autocrine loop in furan-induced rat cholangiocarcinoma cells, and possibly in some forms of human cholangiocarcinoma. It is anticipated that the results generated by the proposed research will contribute in a major way in increasing our understanding of important growth factor-linked alterations related to the development of cholangiocarcinoma in both the rat and human, and will also very likely provide the support for developing new and potentially very effective diagnostic and therapeutic strategies for this highly lethal cancer.